PDF(Pubmed)
Abstract：
Transcriptional coactivator with a PDZ-binding motif (TAZ) plays a key role in normal tissue homeostasis and tumorigenesis through interaction with several transcription factors. In particular, TAZ deficiency causes abnormal alveolarization and emphysema, and persistent TAZ overexpression contributes to lung cancer and pulmonary fibrosis, suggesting the possibility of a complex mechanism of TAZ function. Recent studies suggest that nuclear factor erythroid 2-related factor 2 (NRF2), an antioxidant defense system, induces TAZ expression during tumorigenesis and that TAZ also activates the NRF2-mediated antioxidant pathway. We thus thought to elucidate the cross-regulation of TAZ and NRF2 and the underlying molecular mechanisms and functions. TAZ directly interacted with NRF2 through the N-terminal domain and suppressed the transcriptional activity of NRF2 by preventing NRF2 from binding to DNA. In addition, the return of NRF2 to basal levels after signaling was inhibited in TAZ deficiency, resulting in sustained nuclear NRF2 levels and aberrantly increased expression of NRF2 targets. TAZ deficiency failed to modulate optimal NRF2 signaling and concomitantly impaired lysosomal acidification and lysosomal enzyme function, accumulating the abnormal autophagy vesicles and reactive oxygen species and causing protein oxidation and cellular damage in the lungs. TAZ restoration to TAZ deficiency normalized dysregulated NRF2 signaling and aberrant lysosomal function and triggered the normal autophagy-lysosomal pathway. Therefore, TAZ is indispensable for the optimal regulation of NRF2-mediated autophagy-lysosomal pathways and for preventing pulmonary damage caused by oxidative stress and oxidized proteins.
摘要：
具有PDZ结合基序（TAZ）的转录共激活因子通过与几种转录因子的相互作用在正常组织稳态和肿瘤发生中起关键作用。特别是,TAZ缺乏导致异常肺泡形成和肺气肿，持续的TAZ过表达有助于肺癌和肺纤维化，这表明了TAZ功能的复杂机制的可能性。最近的研究表明，核因子红系2相关因子2（NRF2），抗氧化防御系统,在肿瘤发生过程中诱导TAZ表达，并且TAZ还激活NRF2介导的抗氧化途径。因此，我们认为阐明了TAZ和NRF2的交叉调节以及潜在的分子机制和功能。TAZ通过N末端结构域直接与NRF2相互作用，并通过阻止NRF2与DNA结合来抑制NRF2的转录活性。此外,在TAZ缺乏症中，信号传导后NRF2恢复到基础水平受到抑制，导致持续的核NRF2水平和NRF2靶标表达异常增加。TAZ缺乏未能调节最佳NRF2信号和伴随受损的溶酶体酸化和溶酶体酶功能，积聚异常的自噬囊泡和活性氧，并引起肺中蛋白质氧化和细胞损伤。TAZ恢复到TAZ缺乏使NRF2信号传导失调和溶酶体功能异常并触发正常的自噬-溶酶体途径.因此,TAZ对于NRF2介导的自噬-溶酶体途径的最佳调节以及预防由氧化应激和氧化蛋白引起的肺损伤是必不可少的。
